Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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Extended Nitric Oxide-Releasing Polyurethanes via S‑NitrosothiolModified Mesoporous Silica Nanoparticles Maggie J. Malone-Povolny and Mark H. Schoenfisch* Department of Chemistry, University of North Carolina at Chapel Hill, CB3290, Chapel Hill, North Carolina 27599, United States
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S Supporting Information *
ABSTRACT: S-Nitrosothiol (RSNO)-modified mesoporous silica nanoparticles (MSNs) were doped into polyurethane (PU) to achieve extended NO-releasing coatings. Parameters influencing the synthesis of RSNO-functionalized nitric oxide (NO)-releasing MSNs were evaluated to elucidate the impact of pore structure on NO release characteristics. The porous particles were characterized as having larger NO payloads and longer NO release durations than those of nonporous particles, a feature attributed to the recombination of the NO radical in confined intraporous microenvironments. NO release kinetics, particle leaching, and thermal stability of the RSNO-modified MSNs dispersed in PU were evaluated as a function of PU structure to determine the feasibility of preparing a range of NO-releasing polymers for biomedical devicecoating applications. The NO release kinetics from the PUs proved to be highly extended (>30 d) and consistent over a range of PU properties. Furthermore, RSNO-modified MSN leaching was not observed from the PUs. The NO release payloads were also maintained for 4 days for polymers stored at 0 °C. KEYWORDS: nitric oxide, polyurethane, S-nitrosothiol, silica nanoparticle, mesoporosity
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INTRODUCTION Nitric oxide (NO), an endogenously produced free radical, plays a role in numerous physiological processes, including the inflammatory response, angiogenesis, vasodilation, and antimicrobial and tumoricidal activity.1−5 As a result, much research has focused on the potential benefits of exogenously supplied NO for therapeutic applications. The effects of NO are generally local because of its high reactivity and short lifetime in physiological milieu.6 The role of NO in wound healing has motivated the development of medical device polymeric coatings with NO release capabilities to improve tissue integration and device performance.7−9 Common strategies for the active release of drugs from a medical device include outer coatings doped with traditional antibiotics to limit infection,10 dexamethasone to reduce inflammation,11 or gene therapeutic agents to stimulate vascular growth.12 NO is unique in that it is capable of providing each of these benefits in a single drug release configuration. Development of a range of NO-releasing macromolecular scaffolds, including nanoparticles,13,14 polysaccharides,15,16 and dendrimers,17 has provided NO release systems with a wide array of scaffold characteristics and release profiles to suit multiple medical applications. Silica nanoparticles (SNPs) represent an attractive NOreleasing macromolecular scaffold for medical device coatings. Silica is bioinert, easily functionalizable, and can be readily encapsulated in the polymeric coatings commonly used in the design and fabrication of a given device.18−20 Preliminary studies using SNP-based NO-releasing intravascular catheter © XXXX American Chemical Society
coatings and subcutaneous glucose sensor membranes have shown reduced thrombosis and tissue inflammation, respectively.21,22 The promising results from these studies prompted the development of more efficient and effective NO delivery systems to achieve targeted, tunable, and extended delivery of NO from polymeric coatings. Extended release durations, in particular, have been implicated in better device outcomes: lower thrombosis, improved analyte uptake into microneedles, and decreased inflammatory tissue markers.22−24 Previous works related to NO-releasing SNP-doped coatings have primarily focused on N-diazeniumdiolate (NONOate)modified SNPs.13,22,25 The decomposition rate of NONOates (and liberation of NO) relies on the uptake of water (protons) by the polymer, which imposes a restriction on the design of the system, wherein hydrophobic matrices are required to extend the release of NO. Such requirement is challenging for applications that favor more hydrophilic materials to prevent biofouling (e.g., wound dressings and implanted sensors). In contrast, the use of S-nitrosothiol (RSNO) NO donors does not impose the same design restrictions as NONOates, as the NO release from RSNOs is based on a photothermal decomposition mechanism, independent of water uptake or local pH. Although the lability of RSNOs species allows them to release NO spontaneously under physiological conditions, photothermal instability is detrimental with respect to storage Received: November 2, 2018 Accepted: March 5, 2019
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DOI: 10.1021/acsami.8b19236 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
ACS Applied Materials & Interfaces
room temperature. The solution became cloudy white, indicating particle formation. Particles were washed three times with ethanol and collected by centrifugation. Following the formation of TEOS MSNs, CTAB still present in the pores was removed via ion exchange with ethanolic hydrochloric acid. Particles were dried under vacuum and then treated with oxygen plasma for 2 h to expose surface silanols, facilitating maximum functionalization in subsequent steps. Particles at this point in the synthesis are referred to as pre-grafted MSNs. To functionalize the MSNs with thiol groups, a mercaptosilane (MPTMS) was surface-grafted onto the bare TEOS MSN scaffold. Approximately 50 mg of MSNs was suspended in 20 mL of anhydrous DMF, followed by the addition of 1 μL TEA/mg MSN. The TEA served as a base catalyst. The solution was sonicated to distribute the particles before adding 130 μL of MPTMS/mg MSN as a bolus. The flask was immediately set to reflux at 150 °C for 12 h. The solution was then cooled to room temperature, and the particles were collected by centrifugation with ethanol wash three times and dried under vacuum. The particles at this stage are referred to as post-grafted MSNs. The next step involved nitrosating the particles via exposure to acidified nitrite. Thiol-modified particles (25 mg) were dissolved in a mixture of 5 mL of MeOH and 1 mL of HCl (5 M). An aqueous solution (500 μL) of nitrite (50 mg) and DPTA (10 mg) was then added slowly to the particle solution. This mixture was shielded from light and stirred at 0 °C for 1 h. Particles were then collected by centrifugation and washed with −20 °C MeOH three times. The particle batches were dried under vacuum for 45 min to remove all the remaining MeOH. Nitrosated particles, deep pink in color, were used immediately after removal from the vacuum box. Care was exercised to minimize ambient light exposure during the nitrosation process, as light may prompt the premature release of NO. SNP Physiochemical Characterization. Particle morphology and geometric size were determined using a Hitachi S-4700 cold cathode field emission scanning electron microscope (Pleasanton, CA). Samples in scanning electron micrographs were sputter-coated with 5.0 nm gold/platinum. Specific surface area and pore width of the MSNs were obtained via nitrogen sorption isotherms using a Micrometrics Tristar II 3020 surface area and porosity analyzer (Norcross, GA). Porosimeter samples were dried at 115 °C for 12 h prior to analysis. The specific surface area was assessed using the Brunauer−Emmett−Teller (BET) method using the adsorption isotherm over the p/p0 range of 0.05−0.15. The pore width was measured over the p/p0 range of 0.05−0.60 using the Barrett− Joyner−Halenda (BJH) method. The zeta potential of the particles was determined using a Zetasizer Nano ZS particle size and zeta potential dynamic light-scattering instrument (Malvern, U.K.). Samples were suspended at a concentration of 1 mg mL−1 in phosphate buffer at pH 7.4 and sonicated directly prior to analysis. The Ellman’s assay was used to determine the free thiol content of modified particles.26,36 Known masses of particles were added to a solution of DMSO (2.5 mL), MeOH (2 mL), DIPEA (20 μL), and 10 mM Ellman’s reagent (1.5 mL, in DMSO). A calibration curve was constructed using known concentrations of L-cysteine. Samples were incubated at room temperature for 1 h, followed by absorbance measurements at 412 nm using a LabSystems Multiskan RC plate reader (Helsinki, Finland). Suspension of Porous and Nonporous Particles in PU Membranes. PU solutions were prepared by dissolving PU at a concentration of 80 mg mL−1 into 3:1 anhydrous THF/DMF and sonicating at 60 °C. Upon full dissolution of the polymer, the solution was cooled to room temperature and particles were dispersed into the solution at a range of concentrations (10−80 mg mL−1), sonicating vigorously to ensure homogenous dispersal. PU membranes were deposited by a loop-casting method in the dark on a stainless steel wire to provide uniform coatings of PU. For each layer, 6.5 μL of the PU solution was pipetted onto a 2 mm steel wire loop. This loop was passed over the wire for a total of seven separate coats, with a drying time of 5 min between each coat. An identical coating technique was used to coat sealed glass capillaries to assess the impact of trace metal
of the material. Previous work has emphasized that RSNObased scaffolds are susceptible to ambient light and heat, which poses a challenge for their translation to large-scale commercial distribution.26−28 Mesoporous silica nanoparticles (MSNs) are SNPs with an array of mesochannels that may address the stability challenges commonly associated with RSNO-modified SNPs. The inherently large interior surface area of MSNs may confer additional stability to intraporous RSNO groups because of a phenomenon known as the cage effect. First defined by Franck and Rabinowitch,29,30 the cage effect describes the reduction of radical species formation via geminate recombination within the confines of strong solvent “cages”. These cages are formed by viscous solvents and/or local structural confinement.31,32 In the case of RSNOs, the cage effect favors recombination of the thiyl and NO radical pair after homolytic S−N bond cleavage, extending the duration of NO delivery.33,34 The confined microenvironment provided by the nanometer-scale pores of an MSN may reduce the rate of thermal and photochemical NO release in comparison to RSNO groups found on the exterior surface area of a particle. Herein, we report on the synthesis and characterization of RSNO-functionalized MSNs with extended NO release durations. The physiochemical properties of MSNs are compared to nonporous analogues to elucidate the impact of pores on the NO release properties of the SNP scaffold. In addition, we describe the encapsulation of the RSNOfunctionalized MSNs in a range of polyurethane (PU) coatings to evaluate the role of polymer hydrophobicity on NO release kinetics, particle leaching, and stability.
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EXPERIMENTAL SECTION
Materials. All solvents and reagents were of analytical grade and used as received unless noted otherwise. Dimethyl sulfoxide (DMSO), concentrated hydrochloric acid (HCl), cetyltrimethylammonium bromide (CTAB), triethylamine (TEA), sodium nitrite, diethylenetriaminepentaacetic acid (DPTA), and diisopropylethylamine (DIPEA) were purchased from Sigma-Aldrich (St. Louis, MO). Anhydrous N,N-dimethylformamide (DMF), anhydrous tetrahydrofuran (THF), ammonium hydroxide (NH4OH, 28 wt %), methanol (MeOH), and ethanol (EtOH) were purchased from Fisher Scientific (Fair Lawn, NJ). 5,5′-Dithiobis-(2-nitrobenzoic acid) (Ellman’s reagent) was purchased from Invitrogen Molecular Probes (Eugene, OR). Tetraethylorthosilicate (TEOS) and 3-mercaptopropyltrimethoxysilane (MPTMS) were purchased from Gelest (Morrisville, PA) and stored under nitrogen atmosphere. PUs HP-93A and PC35-85A were received from Lubrizol (Cleveland, OH). PU AL25-80A was received from AdvanSource Biomaterials (Wilmington, MA). Nitrogen (N2), argon (Ar), and NO calibration gas (NO, 25.87 ppm in N2) were purchased from Airgas National Welders (Raleigh, NC). Water was purified using a Millipore Reference water purification system (Bedford, MA) to a resistivity of 18.2 MΩ cm and a total organic content of 50% to 3.29 μmol mg−1, whereas the observed NO payload of the nonporous particles stayed largely the same. The results of the copper-initiated release support the hypothesis that the porous particles do not fully release all of their NO payload under the original incubation conditions. Even though some NO was retained by the MSN scaffold, the NO payload for the porous particles was still nearly twice that of their nonporous counterparts, a clear advantage of porous particles for drug delivery applications. Another major difference between the two particle systems is their NO release kinetics. The porous particles were characterized as having a 26 h half-life and a total release duration of nearly 4 days, representing an unprecedented length of NO release. Generally, the mobility of RSNO groups largely dictates NO release rates, as a thiyl radical must react with an intact RSNO group to avoid recombination with the NO radical.46 In this case, the significant difference in NO release (rates) between porous and nonporous particles of the same size and shape suggests that the porous structure also contributes to the prolonged release durations. Primary RSNO groups within the interior pore surface may exist in solvent cages enforced by the surrounding pore structure. When a confined, intraporous RSNO group undergoes photothermal degradation, the likelihood of recombination of the thiyl and NO radicals before NO can diffuse away appears greater than for exterior RSNO groups. The more extended NO release
degree of functionalization was confirmed via Ellman’s assay, a method that quantifies free thiols. Indeed, the thiol content of the porous particles was more than double that of nonporous particles. From a morphological standpoint, the two particle systems have similar size, shape, and monodispersity but varying surface charge resulting from the degree of surface modification. The NO release kinetics of the two particle systems were compared to evaluate the impact of pore structure on NO storage and stability. NO release parameters were determined using two complementary methods. Although chemiluminescent detection using a NOA allows for real-time NO flux measurements, dynamic initial flux profile, and release kinetics (e.g., half-life) with a relatively low limit of detection (nM), this instantaneous analysis method is not well suited for measuring the lower magnitude NO release typical of stabilized RSNO donors at extended periods. For this reason, the Griess assay, an indirect colorimetric assay that quantifies NO concentrations, was also used to assess NO release over extended periods. Though the Griess assay has a higher limit of detection (0.5 μM), it is only limited by the ability to differentiate between cumulative NO concentrations at successive time points, which allowed profiling of lower NO fluxes. Together, the full NO release profiles of the NOreleasing systems were determined, including total payload ([NO]T), maximum flux ([NO]max), half-life (t1/2), and release duration (td).44 As shown in Table 3, the NO release from the two RSNOfunctionalized SNPs systems was markedly different. Overall, the porous particles had a larger NO payload, longer half-life, and greater release duration than the nonporous analogues. The free thiol content of porous particles correlates directly with the NO payload as more surface thiol groups are available for RSNO conversion. Even after incubation in PBS at 37 °C for ∼100 h, the particles still appeared slightly pink to the eye, evidence of intact primary RSNO groups. These results suggest D
DOI: 10.1021/acsami.8b19236 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
ACS Applied Materials & Interfaces
Table 4. NO Release Measurements of PU Membranes Doped with 80 mg mL−1 of MPTMS/TEOS MSNs in Physiological Buffer (PBS, pH 7.4, 37 °C)a PU
water uptake (mg mg−1)b
[NO]max (ppb cm−2)c
t1/2 (h)d
td (d)e
[NO]T (μmol cm−2)f
HP-93A AL25-80A PC35-85A
2.61 ± 0.12 0.63 ± 0.14 0.18 ± 0.06
254 ± 9 286 ± 14 104 ± 10
37.8 ± 3.1 29.1 ± 4.0 24.0 ± 2.2
33.2 ± 0.3 30.7 ± 0.7 29.5 ± 0.4
4.18 ± 0.24 2.24 ± 0.63 3.94 ± 0.39
Error bars represent standard deviation for n ≥ 3 separate syntheses. bWater uptake expressed as mgwater/mgPU. cMaximum instantaneous NO flux. Half-life of NO release. eNO release duration; time for NO concentrations to reach ≤0.8 pmol cm−2. fTotal NO release.
a
d
with nonporous particles emphasizes the benefit of a poreassociated stabilization to extend release durations in particledoped PUs (Table S2). The duration of NO release also appeared to be independent of PU water uptake properties as the NO half-life and release duration did not trend with PU hydrophobicity. Therefore, RSNO-based NO release may be especially attractive for medical device coatings. Indeed, a PU composition may be selected based on the particular design criteria of a given device application, not by an NO release mechanism. Temperature Stability and Leaching of MSN-Doped PUs. Medical device coatings necessitate robust materials, both prior to and after implantation in the body. The thermal lability of RSNO-particle-doped PU was thus characterized under different storage conditions. Often, the instability of RSNO-based NO release systems under ambient temperature conditions is pointed to as a shortcoming or disadvantage compared to N-diazeniumdiolate NO donors. Membranes capable of ambient temperature storage would make the use of RSNO-based device coatings more appealing. Thermal stability testing was carried out by exposing light-shielded RSNOmodified MSN-doped HP-93A PU membranes to a range of storage conditions (−20, 0, and 23 °C) for 96 h. Prior work has shown that cold storage results in better retention of NO payloads.28,32 As expected, room-temperature storage resulted in reduced NO payloads (Figure 2), whereas membranes stored at −20 and 0 °C showed negligible NO payload loss out to 96 h. Although storage at room temperature eventually leads to lower NO payloads, storage at 0 °C is sufficient for maintaining NO payloads for at least 4 d. Nonporous particle-doped PUs
profile from porous particles also corresponded to a lower maximum NO flux relative to the nonporous particles. Large NO fluxes, as displayed by the nonporous particles and nearly all N-diazeniumdiolate-based SNPs, generally limit NO release duration. Additionally, large NO fluxes are associated with proinflammatory and cytotoxic processes including apoptotic responses and full cell cycle arrest.47−49 Thus, the lowmagnitude, extended NO flux achieved using porous particles holds promise for medical device applications where concerns over lowering inflammation, mitigating infections, and stimulating blood vessel growth are of importance. PU-Based NO Release Using Porous and Nonporous Particles. Dispersion of SNPs in a PU matrix was characterized to assess the ability to create stable NO release polymers for medical devices. PU is a common biomedical material resulting from its inherent bioinertness and robust mechanical properties.50,51 Furthermore, PU is available in a range of hydrophobicities to control water uptake. For example, hydrophobic PU coatings have been shown to reduce the rate of biofouling, thrombosis, and bacterial colonization on catheters, stents, and insulin pumps.52−54 Conversely, hydrophilic PUs are important for certain biosensor designs, where the diffusion of analytes through the polymer matrix is essential for device functionality.55,56 An NO-releasing system capable of consistent NO release across a range of hydrophobicities would potentially allow for expanded medical device utility. Three PU formulations were used as models of very hydrophilic (HP-93A), moderately hydrophilic (AL2580A), and very hydrophobic (PC35-85A) PUs. Nitrosated nonporous and porous particles dispersed in these PU solutions were loop cast onto wire substrates. Loop casting results in a reproducible thin, uniform polymeric layer containing particles.23,57 NO release from membranes cast on analogous glass substrates was consistent with those on the steel wire substrates, indicating that trace metal ions from the wires did not impact NO release (Table S1). Table 4 depicts the NO release characteristics as a function of PU type. Particles doped into PUs were characterized as having prolonged NO release durations and decreased NO fluxes relative to native particles. These changes are attributed to the polymer matrix serving to confine both exterior and intraporous RSNO groups. Little difference between the NO release kinetics of the three different particle-doped membranes was observed, even though the three PUs tested essentially span the range of possible hydrophobicities. Although the maximum NO flux did not trend with hydrophobicity, the three PUs displayed [NO]max values almost an order of magnitude lower than the native particles (Table 3). The confinement imposed by the PU matrix may suppress rapid degradation of exterior RSNO groups responsible for the initial flux of NO from native particles. The relatively limited NO release durations from PUs doped
Figure 2. Storage stability of RSNO-modified MSN-doped HP-93A PU membranes over 96 h at −20 (solid), 0 (striped), and 23 °C (dotted). n ≥ 6 membranes. All significance is in reference to NO release prior to storage (*p < 0.05; **p < 0.01). E
DOI: 10.1021/acsami.8b19236 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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Figure 3. Particle leaching as a function of (A) PU membrane composition with 20 mg mL−1 MSN and (B) MSN concentrations in HP-93A; n ≥ 6 membranes after 21 d soaking in PBS at pH 7.4(*p < 0.05).
previous reports suggesting that a high degree of alkanethiol modification counteracts leaching common to SNPs.38,61 As the degree of thiol modification of the MSNs described is great, the net particle surface charge is almost neutral (Table 1). Furthermore, the particles are hydrophobic because of the nature of the alkanethiol functional groups decorating their surface. This surface hydrophobicity is distinct from that of more highly charged particles (e.g., amine-based NONOates) known to leach over shorter soak periods.38 This negligible leaching may allow for expanded use of RSNO-doped polymeric membranes over extended periods, which has not been possible with alternative N-diazeniumdiolate NO donors.
had similar relative thermal stability versus porous particledoped PUs (Figure S1). The formation of a solvent cage requires the presence of solvent, so the cage effect would not significantly contribute to RSNO stabilization during dry storage. Instead, the increased thermal stability of these NOreleasing materials at lower temperatures is more likely due to decreased thermal mobility of the RSNO functional groups. Overall, enhanced thermal stability is essential for practical NO release applications, including those involving medical device coatings. The stability of the RSNO-modified MSN-doped membranes was also assessed with respect to the final fate of the nanoparticles (i.e., leaching). Although SNPs are often used for their bioinertness, silica can still provoke oxidative stress, tissue injury, and endothelial dysfunction.58−60 The best strategy for avoiding undesirable nanoparticle-associated toxicity is to minimize particle leaching from the membranes. RSNO-modified MSN-doped PU membranes were incubated at 37 °C in PBS at pH 7.4 for 21 d. The extent of particle leaching was determined via elemental analysis (ICP−OES) of silicon in the leachate solution (Figure 3). Comparing across the types of PU, with a constant MSN concentration, the greatest degree of leaching was observed from the most hydrophilic PU, HP-93A. Hydrophilic PUs are known to swell upon water uptake, increasing particle displacement (i.e., leaching).61 To understand the dependence of particle concentration in the membrane on leaching, HP-93A polymers containing 10−80 mg mL−1 were soaked in buffer for 21 d. A concentration of 80 mg mL−1 particles in HP-93A was the largest dopant amount tested as PU did not form a continuous membrane around particles at higher concentrations. Although 80 mg mL−1 membranes demonstrated the greatest percentage of particles leached, leaching from the membranes was at least partially independent of particle concentration. As shown in Figure 3, the least leaching was observed for 20 mg mL−1 particles, while 10 and 40 mg mL−1 particles were statistically equivalent. Increasing hydrophilicity and particle concentration both corresponded with marginally greater leaching magnitudes. Each of the particle-doped PU compositions tested showed negligible leaching (i.e., 30 d are achievable, without particle leaching or the need for extremely cold storage conditions. These attributes present new opportunities for introducing the benefits of NO to a wider range of medical devices, where PU composition selection is often tied to the need or utility of a given device.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.8b19236. NO release from PUs cast on glass; NO release of nonporous particle-doped PU membranes; and storage stability of nonporous particle-doped PU membranes (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: schoenfi
[email protected]. ORCID
Mark H. Schoenfisch: 0000-0002-2212-0658 F
DOI: 10.1021/acsami.8b19236 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
ACS Applied Materials & Interfaces Funding
(16) Pegalajar-Jurado, A.; Wold, K. A.; Joslin, J. M.; Neufeld, B. H.; Arabea, K. A.; Suazo, L. A.; McDaniel, S. L.; Bowen, R. A.; Reynolds, M. M. Nitric Oxide-Releasing Polysaccharide Derivative Exhibits 8Log Reduction against Escherichia Coli, Acinetobacter Baumannii and Staphylococcus Aureus. J. Controlled Release 2015, 220, 617−623. (17) Sun, B.; Slomberg, D. L.; Chudasama, S. L.; Lu, Y.; Schoenfisch, M. H. Nitric Oxide-Releasing Dendrimers as Antibacterial Agents. Biomacromolecules 2012, 13, 3343−3354. (18) Rashti, A.; Yahyaei, H.; Firoozi, S.; Ramezani, S.; Rahiminejad, A.; Karimi, R.; Farzaneh, K.; Mohseni, M.; Ghanbari, H. Development of Novel Biocompatible Hybrid Nanocomposites Based on Polyurethane-Silica Prepared by Sol Gel Process. Mater. Sci. Eng., C 2016, 69, 1248−1255. (19) Ibrahim, I. A. M.; Zikry, A. A. F.; Sharaf, M. A. Preparation of Spherical Silica Nanoparticles: Stöber Silica. J. Am. Sci. 2010, 6, 985− 989. (20) Chen, Y.; Chen, H.; Shi, J. In Vivo Bio-Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles. Adv. Mater. 2013, 25, 3144−3176. (21) Ren, H.; Colletta, A.; Koley, D.; Wu, J.; Xi, C.; Major, T. C.; Bartlett, R. H.; Meyerhoff, M. E. Thromboresistant/Anti-Biofilm Catheters via Electrochemically Modulated Nitric Oxide Release. Bioelectrochemistry 2015, 104, 10−16. (22) Koh, A.; Nichols, S. P.; Schoenfisch, M. H. Glucose Sensor Membranes for Mitigating the Foreign Body Response. J. Diabetes Sci. Technol. 2011, 5, 1052−1059. (23) Wolf, A. K.; Qin, Y.; Major, T. C.; Meyerhoff, M. E. Improved Thromboresistance and Analytical Performance of Intravascular Amperometric Glucose Sensors Using Optimized Nitric Oxide Release Coatings. Chin. Chem. Lett. 2015, 26, 464−468. (24) Soto, R. J.; Privett, B. J.; Schoenfisch, M. H. In Vivo Analytical Performance of Nitric Oxide-Releasing Glucose Biosensors. Anal. Chem. 2014, 86, 7141−7149. (25) Slomberg, D. L.; Lu, Y.; Broadnax, A. D.; Hunter, R. A.; Carpenter, A. W.; Schoenfisch, M. H. Role of Size and Shape on Biofilm Eradication for Nitric Oxide-Releasing Silica Nanoparticles. ACS Appl. Mater. Interfaces 2013, 5, 9322−9329. (26) Riccio, D. A.; Nugent, J. L.; Schoenfisch, M. H. Stöber Synthesis of Nitric Oxide-Releasing S-Nitrosothiol-Modified Silica ParticlesStö. Chem. Mater. 2011, 23, 1727−1735. (27) Frost, M. C.; Meyerhoff, M. E. Synthesis, Characterization, and Controlled Nitric Oxide Release from S-Nitrosothiol-Derivatized Fumed Silica Polymer Filler Particles. J. Biomed. Mater. Res., Part A 2005, 72, 409−419. (28) de Oliveira, M. G.; Shishido, S. M.; Seabra, A. B.; Morgon, N. H. Thermal Stability of Primary S-Nitrosothiols: Roles of Autocatalysis and Structural Effects on the Rate of Nitric Oxide Release. J. Phys. Chem. A 2002, 106, 8963−8970. (29) Rabinowitch, E.; Wood, W. C. The Collison Mechanism and the Primary Photochemical Process in Solutions. Trans. Faraday Soc. 1936, 32, 1381−1387. (30) Franck, J.; Rabinowitsch, E. Free Radicals and the Photochemistry of Solutions. Trans. Faraday Soc. 1934, 30, 120−130. (31) Shishido, S. M.; Seabra, A. B.; Loh, W.; Ganzarolli de Oliveira, M. Thermal and Photochemical Nitric Oxide Release from SNitrosothiols Incorporated in Pluronic F127 Gel: Potential Uses for Local and Controlled Nitric Oxide Release. Biomaterials 2003, 24, 3543−3553. (32) Shishido, S. M.; Oliveira, M. G. Polyethylene Glycol Matrix Reduces the Rates of Photochemical and Thermal Release of Nitric Oxide from S-Nitroso-N-Acetylcysteine. Photochem. Photobiol. 2007, 71, 273−280. (33) Yang, L.; Lu, Y.; Soto, R. J.; Shah, A.; Ahonen, M. J. R.; Schoenfisch, M. H. S-Nitrosothiol-Modified Hyperbranched Polyesters. Polym. Chem. 2016, 7, 7161−7169. (34) Stasko, N. A.; Fisher, T. H.; Schoenfisch, M. H. S-NitrosothiolModified Dendrimers as Nitric Oxide Delivery Vehicles. Biomacromolecules 2008, 9, 834−841.
This research was supported by the National Institutes of Health (DK108318). Notes
The authors declare the following competing financial interest(s): Mark Schoenfisch maintains financial interest in Clinical Sensors, Inc. and Novan, Inc. Clinical Sensors is developing NO-releasing sensors membranes for continuous glucose monitoring devices. Novan is commercializing NOreleasing macromolecular vehicles for dermatological indications.
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ACKNOWLEDGMENTS This work was performed in part at the Chapel Hill Analytical and Nanofabrication Laboratory, CHANL, a member of the North Carolina Research Triangle Nanotechnology Network, RTNN, which is supported by the National Science Foundation, Grant ECCS-1542015, as part of the National Nanotechnology Coordinated Infrastructure, NNCI.
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